The hypothetical basis for this program project is to understand the relationship between the underlying genetic variants and the innate and adaptive immune response in the pathogenesis of Crohn's disease. Exposure to commensal bacteria and/or concomitant mucosal injury likely leads to markedly decreased protection and a greatly increased bacterial exposure. Depending on the presence of any additional genetic defects, which either produce a defective T or B regulatory cell population or a potent effector T-cell population and/or abnormal cytokine regulation, these conditions would lead to a markedly increased Th1 adaptive immune response, which would be associated with very severe, rapidly progressive mucosal inflammation in humans and rodents. The advances in the field, focused by the multiple contributions from this program project form the foundation of this paradigm, which should allow us to address the underlying genetic variants (Project 1) and immunophysiologic abnormalities in innate immune, Th1 effector, and/or T and B regulatory cell populations (Projects 1, 2 and 3) or T cell co-stimulatory pathways (Project 4), associated with these adaptive immune responses in both mouse and man. Instead of using classifications like "Crohn's disease" or anatomical or clinical phenotypes, we would do better to use immune response as a marker for associated underlying genetic variants and abnormal immune responses. The underlying genetics will be investigated in Project 1, "A candidate gene approach to immuno-phenotypic subgroups of Crohn's disease," J. Rotter, PI. The relationship between the innate and adaptive immune responses and their role in mucosal inflammation will be studied in Project 2, "Immunopathologic mechanisms leading to an aggressive Crohn's disease immuno-phenotype," S. Targan, PI. The effect mucosal B cells on mucosal inflammmation will be investigated in Project 3, "Translational assessment of B cell immunoregulation in human Crohn's disease patient subsets," J Braun, PI. The role of costimulatory molecules in colitis pathogenesis will be studied in Project 4, "Colitis induced by alterations in B7 mediated costimulation," M. Kronenberg, PI. By achieving the goals delineated in this proposal, we will have a much clearer understanding of the genetic factors and immunologic processes involved in aggressive/progressive animal and Crohn's disease mucosal inflammation. We will understand the genetic variants that underlie the relationship between alteration in innate immune functions, heightened T cell co-stimulation, excessive Th1 and IFN-gamma generation, and T and B cell regulatory functions and high level serologic responses to microbial antigens with aggressive/ progressive mucosal inflammation. Because of the intention of this program project to include both human and animal investigations, progress will be accelerated by the interplay between projects. Core B will be central and critical for the accomplishment of these objectives of human and animal studies.